Abstract 3405: DPF3 - a Novel Epigenetic Regulator of Cardiac and Skeletal Muscle Development
Chromatin remodeling and histone modifications can have a high impact on cardiac function and development. Both facilitate access of transcription factors to DNA by promoting the unwinding and destabilization of histone-DNA interactions. We present DPF3, a novel epigenetic key factor for heart and muscle development, which first came to our interest by being differentially expressed in cardiac tissue of patients with Tetralogy of Fallot. Taking a systematic approach including methods such as in situ hybridization, electron-microscopy, gene expression arrays, siRNA knock-down, morpholino treatment, reporter gene assays, EMSA, chromatin-immunoprecipitation with array detection (ChIP-chip), GST pulldown and TAP-tag, we were able to elucidate the function and role of DPF3. DPF3 is associated with the BAF chromatin remodeling complex and binds methylated and acetylated lysine residues of histone 3 and 4. Thus, DPF3 represent the first plant-homeodomains that bind acetylated lysines, a feature previously only shown for the bromodomain. During development Dpf3 is expressed in the heart and somites of mouse, chicken and zebrafish. Morpholino knockdown of dpf3 in zebrafish leads to incomplete cardiac looping and severely reduced ventricular contractility with disassembled muscular fibers caused by transcriptional deregulation of structural and regulatory proteins. Morphants show a deregulation of myofibrillar proteins, regulators of sarcomere assembly such as cyma1 (cardiomyopathy associated1), actin capping protein capZ as well as cardiac transcription factors, id2 and hand2. Interestingly, the dpf3 morphant phenotype resembles in part the defects seen in mef2a morphants and Mef2a-deficient mice. Further promoter analysis identified Dpf3 as a novel downstream target of Mef2a. Taken together, DPF3 further explains the high impact of the histone modification status on cardiac development and function.